As life expectancy increases, Alzheimer's disease (AD) is becoming a major health problem in the western world. There has been intensive research aimed at identifying a reliable cure or preventive measures for the disease, so far without success.
It is becoming widely accepted that cell cycle re-entry and subsequent regulatory failure in neurons is at the pathogenic basis of Alzheimer's disease (Nagy, Z., M. M. Esiri, and A. D. Smith, The cell division cycle and the pathophysiology of Alzheimer's disease. Neuroscience, 1998. 84(4): p. 731-739; also applicant's published International patent application WO 02/073212). There are also indications that this regulatory dysfunction of the cell division cycle is not restricted to the neurons of Alzheimer's disease patients (Nagy, Z., et al., Cell cycle kinesis in lymphocytes in the diagnosis of Alzheimer's disease. Neurosci Lett, 2002. 317(2): p. 81-4). There is evidence that other cell types, such as lymphocytes and fibroblasts, originating from Alzheimer's disease sufferers have deficient cell cycle regulatory machinery. This regulatory deficiency leads to aberrant response of these cells to various in vitro stimuli (see WO 02/073212). Furthermore, Alzheimer's disease patients are more prone to certain types of cancers than the age matched control subjects. On the basis of this evidence, it is plausible that the regulatory failure on the G1/S transition point responsible for the development of AD-related pathology in neurons is due to mutations or allelic variations of the cell cycle regulatory genes, particularly the cyclin-dependent kinase inhibitors or CDKIs.
Since cell cycle disturbances seem to be a very, early event in Alzheimer's disease, preceding the development of any clinical symptoms, the identification of mutations and polymorphisms in cell cycle regulatory genes will allow the identification of patients who do not have fully developed Alzheimer's disease but may be at increased risk of developing the disease. This may in turn allow early intervention with strategies aimed at preventing the development and/or delaying the onset of Alzheimer's disease pathology.
The human cyclin-dependent kinase inhibitor-1A gene (OMIT accession number 1 16 899, referred to herein as p21cip 1, OMIT nomenclature CDKN1A, also known in the art as CDK-interacting protein 1, CIP1, p21, wildtype p53-activated fragment 1, or WAFT) is one of the CDKI genes responsible for the regulation of the G1/S transition point. The gene encodes a 21-kd protein that is found in immunoprecipitates of cyclin A, cyclin D1, cyclin E, and CDK2. The p21cip 1 gene has been mapped to 6p21.2 by fluorescence in situ hybridization.
A polymorphism has been identified at codon 31 of p21cip 1 (Chedid, M. et al., Oncogene, Vol 9(10), 3021-4, 1994), where a single point mutation changes the normal or “wild-type” allele AGC (ser) to a variant allele AGA (arg). The OMIM accession number for this polymorphism (referred to herein as p21E2c31) is 116899.0001. The single nucleotide substitution results in the loss of a restriction site and gain of another, allowing for rapid screening of the polymorphism (Chedid, M. et al., 1994, ibid). Analysis of the polymorphism has revealed that it is related to an increased risk of certain types of cancer (Harima, Y., et al., Polymorphism of the WAF1 gene is related to susceptibility to cervical cancer in Japanese women. Int J Mol Med, 2001. 7(3): p. 261-4). A further single nucleotide polymorphism in the p21 gene, a C to T transition occurring 20 nucleotides downstream of the 3′ end of exon 3 (referred to herein as p21E3+20 C/T) is also known to be associated with cancer (Facher, E. A., et al., Association between human cancer and two polymorphisms occurring together in the p21Waf1/Cip1 cyclin-dependent kinase inhibitor gene. Cancer, 1997. 79(12): p. 2424-9).
The present inventor has now demonstrated that the p21E2c31 polymorphism shows a significant association with Alzheimer's disease. Furthermore, co-occurrence of the p21E2c31 polymorphism with the p21E3+20 C/T polymorphism improves the significance of the association with Alzheimer's disease. These observations have led to the development of novel genetic screens which may be used to identify individuals genetically predisposed to developing Alzheimer's disease.